From Notochord Formation to Hereditary Chordoma: The Many Roles of<i>Brachyury</i>

Nibu, Yutaka; José-Edwards, Diana S.; Gregorio, Anna Di

doi:10.1155/2013/826435

Cited by 86 publications

(73 citation statements)

References 175 publications

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“…Our results show the presence of two distinct MPC populations in the tailbud: one that contributes to hypochord and notochord and a second that gives rise to notochord and floor plate. This work will provide insight into poorly understood human diseases associated with defective notochord development, including SNS and the rare but highly lethal cancer chordoma (Nibu et al, 2013;Yazici et al, 2014). Chordoma is an aggressive tumor type found along the axis of the body, and is thought to be derived from notochord remnants that persist from embryonic stages into adulthood (Nibu et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The zebrafish tailbud contains two independent populations of midline progenitor cells that maintain long-term germ layer plasticity and differentiate based on local signaling cues

et al. 2015

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Vertebrate body axis formation depends on a population of bipotential neuromesodermal cells along the posterior wall of the tailbud that make a germ layer decision after gastrulation to form spinal cord and mesoderm. Despite exhibiting germ layer plasticity, these cells never give rise to midline tissues of the notochord, floor plate and dorsal endoderm, raising the question of whether midline tissues also arise from basal posterior progenitors after gastrulation. We show in zebrafish that local posterior signals specify germ layer fate in two basal tailbud midline progenitor populations. Wnt signaling induces notochord within a population of notochord/floor plate bipotential cells through negative transcriptional regulation of sox2. Notch signaling, required for hypochord induction during gastrulation, continues to act in the tailbud to specify hypochord from a notochord/hypochord bipotential cell population. Our results lend strong support to a continuous allocation model of midline tissue formation in zebrafish, and provide an embryological basis for zebrafish and mouse bifurcated notochord phenotypes as well as the rare human congenital split notochord syndrome. We demonstrate developmental equivalency between the tailbud progenitor cell populations. Midline progenitors can be transfated from notochord to somite fate after gastrulation by ectopic expression of msgn1, a master regulator of paraxial mesoderm fate, or if transplanted into the bipotential progenitors that normally give rise to somites. Our results indicate that the entire non-epidermal posterior body is derived from discrete, basal tailbud cell populations. These cells remain receptive to extracellular cues after gastrulation and continue to make basic germ layer decisions.

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Section: Discussionmentioning

confidence: 99%

The zebrafish tailbud contains two independent populations of midline progenitor cells that maintain long-term germ layer plasticity and differentiate based on local signaling cues

et al. 2015

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“…As the name implies, chordomas are thought to be of notochordal origin and one of the major roles of T is in the development of the notochord (Nibu et al, 2013). T has also been implicated in controlling EMT in some cancers such as adenoid cystic carcinoma and colorectal cancer (Sarkar et al, 2012;Shimoda et al, 2012).…”

Section: Cip1mentioning

confidence: 99%

The T-box gene family: emerging roles in development, stem cells and cancer

2014

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The T-box family of transcription factors exhibits widespread involvement throughout development in all metazoans. T-box proteins are characterized by a DNA-binding motif known as the T-domain that binds DNA in a sequence-specific manner. In humans, mutations in many of the genes within the T-box family result in developmental syndromes, and there is increasing evidence to support a role for these factors in certain cancers. In addition, although early studies focused on the role of T-box factors in early embryogenesis, recent studies in mice have uncovered additional roles in unsuspected places, for example in adult stem cell populations. Here, I provide an overview of the key features of T-box transcription factors and highlight their roles and mechanisms of action during various stages of development and in stem/progenitor cell populations.

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“…Numerous subsequent studies confirmed that the coordinated expression of the T gene during gastrulation is essential for appropriate notochord, neural tube, and mesoderm development (Chesley 1935;Pennimpede et al 2012;Satoh et al 2012). Recently, the T gene has gained interest because of its association with the human chordoma, a sporadic and hereditary tumor originating from relicts of the notochord (Yang et al 2009;Pillay et al 2012;Nibu et al 2013). Thus, the T gene is a prime candidate for investigating phenotypic alterations of the vertebral column and spinal cord.…”

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confidence: 99%

The Mammalian Cervical Vertebrae Blueprint Depends on theT(brachyury) Gene

Kromik

Ulrich²,

Kusenda

et al. 2015

Genetics

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A key common feature of all but three known mammalian genera is the strict seven cervical vertebrae blueprint, suggesting the involvement of strong conserving selection forces during mammalian radiation. This is further supported by reports indicating that children with cervical ribs die before they reach reproductive age. Hypotheses were put up, associating cervical ribs (homeotic transformations) to embryonal cancer (e.g., neuroblastoma) or ascribing the constraint in cervical vertebral count to the development of the mammalian diaphragm. Here, we describe a spontaneous mutation c.196A . G in the Bos taurus T gene (also known as brachyury) associated with a cervical vertebral homeotic transformation that violates the fundamental mammalian cervical blueprint, but does not preclude reproduction of the affected individual. Genome-wide mapping, haplotype tracking within a large pedigree, resequencing of target genome regions, and bioinformatic analyses unambiguously confirmed the mutant c.196G allele as causal for this previously unknown defect termed vertebral and spinal dysplasia (VSD) by providing evidence for the mutation event. The nonsynonymous VSD mutation is located within the highly conserved T box of the T gene, which plays a fundamental role in eumetazoan body organization and vertebral development. To our knowledge, VSD is the first unequivocally approved spontaneous mutation decreasing cervical vertebrae number in a large mammal. The spontaneous VSD mutation in the bovine T gene is the first in vivo evidence for the hypothesis that the T protein is directly involved in the maintenance of the mammalian seven-cervical vertebra blueprint. It therefore furthers our knowledge of the T-protein function and early mammalian notochord development.KEYWORDS homeotic transformation; genetic defect; brachyury H IGH evolutionary diversification of the vertebral column exists in vertebrates, but the number of cervical vertebrae within mammals has been fixed at seven for .200 million years of evolution since the beginning of the long and wide mammalian radiation (Hautier et al. 2010). The reason why all mammals share this fundamental blueprint of cervical vertebrae, compared with a more relaxed rule for the number of posterior vertebrae analogous to other nonmammalian vertebrates, remains unknown. Nevertheless, evolutionary and clinical data indicate that the cervical vertebral development of mammals is under high selection pressure. For example, in human pediatrics, 83% of children with a deviating number of cervical vertebrae die in their first year, while the surviving individuals do not reach reproductive age (Galis et al. 2006). A detailed knowledge of the key factors involved in the spatial regulation of vertebral development will help to understand these forces.Mutation models, either spontaneous or artificially induced, can reveal the complex processes that occur during vertebral development. Vertebral and accompanied spinal defects are described for many species, including cattle [e.g., complex vert...

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From Notochord Formation to Hereditary Chordoma: The Many Roles ofBrachyury

Cited by 86 publications

References 175 publications

The zebrafish tailbud contains two independent populations of midline progenitor cells that maintain long-term germ layer plasticity and differentiate based on local signaling cues

The zebrafish tailbud contains two independent populations of midline progenitor cells that maintain long-term germ layer plasticity and differentiate based on local signaling cues

The T-box gene family: emerging roles in development, stem cells and cancer

The Mammalian Cervical Vertebrae Blueprint Depends on theT(brachyury) Gene

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